Pain is a protective mechanism warning that the body needs medical help. Actually at least half of patients see doctors because they suffer from pain. However, chronic pain does not display protective significance but seriously bothers people's life. Existing analgesics either are not very effective or produce serious adverse effects, or both. For example, opioids induce constipation and inhibit respiration. There is also an abuse potential with opiates, and the fear of dependence reduces compliance for this class of drugs. The COX-2 inhibitors family has been plagued by a number of adverse effects, some of which are even lethal. The old stand-by NSAIDs are also plagued by lethal serious adverse effects. Therefore, there is a competitive advantage in developing a drug that targets peripheral receptors because it would lacks CNS adverse effects.
It has been documented that many receptors in the periphery are involved in induction or modulation of pain, such as opioid (Hong & Abbott, 1995;Yaksh, 1997), glutamate (Carlton, 2001;Neugebauer, 2001), CB1 and CB2 (Palmer et al., 2002), prostaglandin (Francischi et al., 2002;Ito et al., 2001) etc. Activation or inhibition of these receptors suppresses pain, indicating that it is feasible to target peripheral receptors to relieve pain.
Inflammatory and injured pain is induced following the activation of primary sensory neurons. It is a variety of chemical mediators released during inflammation that maintains activity of primary afferents and/or enhances nociceptor sensitivity leading to hyperalgesia or allodynia. 5-HT (5-hydroxytryptamine or serotonin) is one of inflammatory mediators (Foon et al., 1976), playing a key role in the development of pain (Hong & Abbott, 1994). This chemical is released from platelets, mast cells and endothelial cells into a wound site after tissue injury and inflammation (Parada et al., 2001;Rowley, 1956). 5-HT activates c-fiber afferents (Beck & Handwerker, 1974;Herbert & Schmidt, 1992;Grubb et al., 1988), increases excitability of small-diameter neurons in the dorsal root ganglia (Cardenas et al., 2001) and release CGRP (Tramontana et al., 1993), indicating that it is a pro-algesic or nociceptive agent. 5-HT itself is involved in the induction of pain as application of 5-HT to the blister base or skin in humans causes pain sensation (Jensen et al., 1990a; Jensen et al., 1990b;Armstrong et al., 1953;Richardson et al., 1985;Orwin & Fozard, 1986). It has been documented that the high plasma 5-HT level is associated with adjuvant arthritis. (Pertsch et al., 1993). 5-HT can be ascribed for NGF-induced inflammation and hyperalgesia as NGF causes degranulation of mast cells and releases 5-HT (Horigome et al., 1993;Lewin et al., 1994). Furthermore, 5-HT sensitizes nociceptive responses evoked by mechanical, thermal and chemical stimuli, inducing pain (Vinegar et al., 1989;Rang et al., 1991;Hong & Abbott, 1994;Schmelz et al., 2003) or potentiating pain produced by other inflammatory mediators, such as substance P. noradrenaline. prostaglandin E2, bradykinin, etc. in animals (Hong & Abbott, 1994;Khalil & Helme, 1990) and humans (Jensen et al., 1990a;Jensen et al., 1990b; Sicuteri et al., 1965;Bleehen & Keele, 1977;Babenko et al., 1999). These may underlie the key role of 5-HT in pain associated with tissue injury and inflammation (Holsapple et al., 1980;Hong & Abbott, 1994;Di Rosa et al., 1971;Khalil & Helme, 1990).
5-HT interacts with multiple subtypes of 5-HT receptors in the periphery to produce nociception, among which 5-HT2A receptor is pivotal. This notion is based on the facts that serotonin-induced hyperalgesia and enhancement on pain produced by noradrenaline and prostaglandin E2 are mimicked by 5-HT2A receptor agonists, but not by the agents acting at 5-HT1A and 5-HT3 receptors. Correspondingly, nociceptive response induced by serotonin is specifically abolished by 5-HT2A receptor antagonist, but not by the blockade of 5-HT1A and 5-HT3 receptors. (Grubb et al., 1988;Abbott et al., 1996;Doi-Saika et al., 1997;Tokunaga et al., 1998). 5-HT2A receptor antagonist, ketanserin, also profoundly suppresses serotonin-induced plasma extravasation in the knee joint model of inflammation as well (Pierce et al., 1995). Particularly, the mediation of 5-HT2A receptor in pain has been demonstrated in the widely used pain models, such as formalin test (Abbott et al., 1997), CFA (Okamoto et al., 2002) and carrageenan (Wei et al., 2005) models of inflammation and arthritis (Pertsch et al. 1993). In addition, 5-HT2A receptor is involved in the development of hyperalgesia and edema induced by the nociceptive mediator adenosine (Sawynok et al., 1997).
As inflammatory site is actually a source for the development and maintenance of pain, pain may be relieved by targeting the 5-HT2A receptor in this local site. This can be achieved by local or systemic injection of 5-HT2A antagonists. More importantly, we have found that combination of two compounds that target two different receptors produces synergistic antinociception. Our results have demonstrated that targeting two receptors has produced a significant inhibition on nociceptive responses in animal studies. This analgesic drug targets two novel targets. Either of the compounds selectively targets their respective receptor and produces potent analgesic in inflammatory pain with rapid onset and lack of adverse effects. Each drug produces a naloxone-reversible hypoalgesia suggesting the activation of an endogenous opioid mechanism. Interestingly, when the two compounds are administered together, lower doses of each compound can elicit the significant antinociceptive effects. Moreover, both local and systemic injections of the combination are equally effective. The combination also did not induce overt adverse effects or tolerance to the drugs. Furthermore, the combination is effective in relieving neuropathic pain which is not even responsive to opioids sometimes. Preclinical tests have been completed and potential applications of this combination include arthritis, muscleskeletal pain syndrome, general inflammatory pain and neuropathic pain. The results that were obtained in this laboratory are summarized below. It should he addressed that our goal was to develop good analgesic without site effects. This new drug does not have to be better than morphine for inhibition of nociception. Therefore, the comparison with morphine or other powerful existing analgesic has not been designed.